Toxoplasma Polymorphic Effectors Determine Macrophage Polarization and Intestinal Inflammation

Abstract

SUMMARY European and North American strains of the parasite Toxoplasma gondii belong to three distinct clonal lineages, type I, II and III, which differ in virulence. Understanding the basis of Toxoplasma strain differences and how secreted effectors work to achieve chronic infection is a major goal of current research. Here we show that type I and III infected macrophages, a cell type required for host immunity to Toxoplasma, are alternatively activated, while type II infected macrophages are classically activated. The Toxoplasma rhoptry kinase ROP16, which activates STAT6, is responsible for alternative activation. The Toxoplasma dense granule protein GRA15, which activates NF-κB, promotes classical activation by type II parasites. These effectors antagonistically regulate many of the same genes, and mice infected with type II parasites expressing type I ROP16 are protected against Toxoplasma-induced ileitis. Thus, polymorphisms in determinants that modulate macrophage activation influence the ability of Toxoplasma to establish a chronic infection.

GRA25 Is a Novel Virulence Factor of Toxoplasma gondii and Influences the Host Immune Response

“…Gene Set Enrichment Analysis (GSEA) (27) and distal regulatory element enrichment (DiRE) analysis (http://dire.dcode.org/) of the mouse genes that mapped to Toxoplasma chromosome VIIb indicated that their transcription was largely controlled by transcription factors STAT3, STAT5, and STAT6, which are targets of ROP16. These results indicate that ROP16 likely plays an important role in mediating strain-specific differences in macrophage gene expression as it does in fibroblasts, a finding that has been experimentally validated in macrophage studies using ROP16-deficient parasites (14,18,28).…”

“…As the interactions between an invading parasite and its host cell likely differ in different cell types and different host species, we hypothesized that analysis of gene expression in macrophages from the mouse, a host that has a long evolutionary history with Toxoplasma and a cell type that is crucial for innate immunity, would reveal previously unidentified parasite effectors that specifically modulate these key initiators of the immune response. Indeed, studies in mouse macrophages have shown that the known Toxoplasma effectors account for only about 40% of the strain-specific differences in gene expression observed when macrophages are infected with type II versus type III parasites (18). To identify previously unknown effectors, therefore, we have used type II versus type III F1 progeny to map parasite loci responsible for changes in mouse macrophage gene expression induced upon infection.…”

Functional Annotation of Intrinsically Disordered Domains by Their Amino Acid Content Using Idd Navigator

“…Moreover, it was argued that GRA15-II is likely to act in a complex with the kinase IKK and signaling protein TRAF6 21 , which are important regulators of the NF-B signaling pathway. GRA15-II-mediated NF-B activation in macrophages inhibited apoptosis, and increased cell migration 20,21 . These known biological functions of GRA15-II are overall consistent with the IDD Navigator results.…”

“…The effect of GRA15 on the host immune system depends on the particular T. gondii strain (types I-III). Recently, the effects of type II GRA15 (GRA15-II) on host immune signaling pathways have been described 20,21 . No hits to GRA15 were found using conventional sequence alignment searches 21 .…”

Molecular Mechanisms Used by Salmonella to Evade the Immune System

“…This subset of macrophages does not express many of the defence mechanisms needed to eliminate invading microbes. Moreover, there are pathogens that have developed strategies to induce polarization of cells towards the M2 phenotype as a virulence mechanism ( Jensen et al, 2011).…”